Derivatives of Dibenzothiophene for Positron Emission Tomography Imaging of α7-Nicotinic Acetylcholine Receptors

A new series of derivatives of 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)dibenzo[b,d]thiophene 5,5-dioxide with high binding affinities and selectivity for alpha 7-nicotinic acetylcholine receptors (alpha 7-nAChRs) (K-i = 0.4-20 nM) has been synthesized for positron emission tomography (PET) imaging of alpha 7-nAChRs. Two radiolabeled members of the series [F-18]7a (K-i = 0.4 nM) and [F-18]7c (K-i = 1.3 nM) were synthesized. [F-18]7a and [F-18]7c readily entered the mouse brain and specifically labeled alpha 7-nAChRs. The alpha 7-nAChR selective ligand 1 (SSR180711) blocked the binding of [F-18]7a in the mouse brain in a dose-dependent manner. The mouse blocking studies with non-alpha 7-nAChR central nervous system drugs demonstrated that [F-18]7a is highly alpha 7-nAChR selective. In agreement with its binding affinity the binding potential of [F-18]7a (BPND = 5.3-8.0) in control mice is superior to previous alpha 7-nAChR PET radioligands. Thus, [F-18]7a displays excellent imaging properties in mice and has been chosen for further evaluation as a potential PET radioligand for imaging of alpha 7-nAChR in non-human primates.